EP2010143A2 - Stabilized ophthalmic compositions comprising oxidatively unstable components - Google Patents

Stabilized ophthalmic compositions comprising oxidatively unstable components

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Publication number
EP2010143A2
EP2010143A2 EP07758669A EP07758669A EP2010143A2 EP 2010143 A2 EP2010143 A2 EP 2010143A2 EP 07758669 A EP07758669 A EP 07758669A EP 07758669 A EP07758669 A EP 07758669A EP 2010143 A2 EP2010143 A2 EP 2010143A2
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EP
European Patent Office
Prior art keywords
stabilizing agent
μmoles
acid
liter
ophthalmic composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP07758669A
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German (de)
French (fr)
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EP2010143B1 (en
Inventor
Shivkumar Mahadevan
Frank Molock
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Johnson and Johnson Vision Care Inc
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Johnson and Johnson Vision Care Inc
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Publication of EP2010143A2 publication Critical patent/EP2010143A2/en
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Publication of EP2010143B1 publication Critical patent/EP2010143B1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • Therapeutic agents for topical administration to the eye are generally formulated in either a liquid or gel form and must be kept sterile until administration. Accordingly, ophthalmic therapeutic agents are either packaged asceptically, which is cumbersome and expensive or are heat sterilized. Unfortunately, many therapeutic agents are not oxidatively stable, especially at elevated temperatures.
  • This invention includes a method of stabilizing an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient wherein said method comprises adding an effective amount of a stabilizing agent to the ophthalmic composition.
  • oxidatively unstable pharmaceutical ingredient refers to pharmaceutical or nutraceutical compounds used to treat conditions of the eye, and such compound degrade in the presence of oxygen and certain transition metals.
  • pharmaceutical compounds include antihistamines, antibiotics, antibacterial agents, antiviral agents, antifungal agents, analgesics, anesthetics, antiallergeneic agents, mast cell stabilizers, steroidal and non- steroidal anti-inflammatory agents, angiogenesis inhibitors; antimetabolites, fibrinolytics, neuroprotective drugs, angiostatic steroids, mydriatics, cyclopegic mydriatics; miotics; vasoconstrictors; vasodilators, anticlotting agents; anticancer agents, antisense agents, immunomodulatory agents, carbonic anhydrase inhibitors, integhn antabonistsl; cyclooxygenase inhibitors, VEGF antagonists; immunosuppressant agents and the like.
  • examples of pharmaceutical agents include but are not limited to achvastine, antazoline, astemizole, azatadine, azelastine, buclizine, bupivacaine, cetirizine, clemastine, cyclizine, cyproheptadine, ebastine, emedastine, ephedrine, eucatropine, fexofenadine, homatropine, hydroxyzine, ketotifen, levocabastine, levoceterizine, lomefloxacin, meclizine, mepivacaine, mequitazine, methdilazine, methapyrilene, mianserin, naphazoline norastemizole, norebastine, ofloxacin, oxymetazoline, pheniramine, phenylephrine, physostigmine, picumast, promethazine, scopolamine, terfen
  • Preferred pharmaceutical compounds include achvatine, antazoline, astemizole, azatadine, azelastine, clemastine, cyproheptadine, ebastine, emedastine, eucatropine, fexofenadine, homatropine, hydroxyzine, ketotife, levocabastine, levoceterizine, meclizine, mequitazine, methdialazine, methapyrilene, norastemizole, norebastine, oxymetazoline, physootigmine, picumast, promethazine, scopolamine, terfenadine, tetrahyerozoline, fimilol, trimeprazine, triprolidine, and pharmaceutically acceptable salts thereof.
  • Particularly preferred pharmaceutical compounds include phenarimine, ketotifen, ketotifen fumarate nor ketotifen, olapatadine and mixtures thereof. More particularly preferred pharmaceutical compounds include ketotifen, its pharmaceutically acceptable salts, and mixtures thereof.
  • nutraceutical compounds include vitamins and supplements such as vitamins A, D, E, lutein, zeaxanthin, lipoic acid, flavonoids, ophthalmicially compatible fatty acids, such as omega 3 and omega 6 fatty acids, combinations thereof, combinations with pharmaceutical compounds and the like.
  • Preferred pharmaceutical or nutraceutical compounds are those that degrade when solutions of these compounds and oxidative catalysts (such as metals and metallic salts) are mixed together at ambient or elevated temperatures, as compared to solutions of these compounds without oxidative catalysts at ambient or elevated temperatures.
  • Particularly preferred pharmaceutical or nutraceutical compounds are those that degrade greater than about 10% when heated to about 12O 0 C for about 20 minutes with oxidative catalysts.
  • the concentration of oxidatively unstable pharmaceutical ingredients in the ophthalmic compositions of the invention range from about 2 ⁇ g/mL to about 0.5 g/mL, particularly preferred, about 0.1 ⁇ g/mL to about 10,000 ⁇ g/mL.
  • ophthalmic composition refers to liquids, aerosols, or gels that may be topically administered to the eye.
  • stabilizing agent refers to chelant compositions that inhibit metal catalyzed oxidative degradation of the oxidatively unstable pharmaceutical ingredient.
  • stabilizing agents include but are not limited to silica, chitin derivative such as chitosan, polyamides such as poly(aspartic acid-co- ⁇ -amino acid (See CAN:129:54671 , Shibata, Minako et al. graduate School Environmental Earth Science,
  • polymeric amides such as poly[iminocarbonyl(2,5-dihydroxy- 1 ,4-phenylene)carbonylimino-1 ,4-phenylenemethylene-1 ,4-phenylene], CAS # 87912-00-3, polymeric lactams such as polyvinylpyrrolidone, polyamino carboxylic acids such as diethylenethaminepentaacetic acid and triethylenetriaminepentaacetic acid, polymeric amines such as polyallylamine, crown ethers such as 18-crown-6, 21 -crown-7, and 24-crown-8, cellulose and its derivatives, and N, N, N', N', N", N"-hexa(2-pyridyl)-1 ,3,5- ths(aminomethyl)benzene, and certain macrocyclic ligands such as crown ethers
  • the preferred stabilizing agents are polyamino carboxylic acids such as diethylenetriaminepentaacetic acid and triethylenetriaminepentaacetic acid.
  • the particulary preferred stabilizing agents are diethylenetriaminepentaacetic acid ("DTPA"), or salts of DTPA such as CaNa 3 DTPA, ZnNa 3 DTPA, and Ca 2 UTPA.
  • the term "effective amount” refers to the amount of stabilizing agent required to inhibit the oxidative degradation of the pharmaceutical ingredient. In most circumstances it is preferred that there is a 1 :1 molar ration of metal present in the ophthalmic composition to chelant, is more preferably about 1 of metal to greater than about 1 of chelant compositions, most preferably about 1 of metal to greater than or equal to about 2 of chelant compositions.
  • the stabilizing agents have a concentration in the ophthalmic composition from about 2.5 ⁇ moles/liter to about, 5000 ⁇ moles/liter more preferably from about 20 ⁇ moles/liter to about 1000 ⁇ moles/liter, more preferably from about 100 ⁇ moles/liter to about 1000 ⁇ moles/liter, most preferably from about 100 ⁇ moles/liter to about 500 ⁇ moles/liter.
  • the ophthalmic composition contains suitable ophthalmic carriers.
  • suitable carriers include antioxidants (radical scavengers), demulcents, antibacterial agents, solubilizers, surfactants, buffer agents, tonicity adjusting agents, chelating agents, preservatives, wetting agents, thickeners, water, saline solution, mineral oil, petroleum jelly, water soluble solvents, such as Ci 5- 2o alcohols, Ci 5- 2o amides, Ci 5- 2o alcohols substituted with zwittehons, vegetable oils or mineral oils comprising from 0.5 to 5% by weight hydroxyethylcellulose, ethyl oleate, carboxymethylcellulose, polyvinyl- pyrrolidone and other non-toxic water-soluble polymers for ophthalmic uses, such as, for example cellulose derivatives, such as methylcellulose, alkali metal salts of carboxy-methylcellulose, hydroxymethylcellulose, hydroxyethyl
  • Poloxamer F127 polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably cross-linked poly(acrylic acid), such as neutral Carbopol, or mixtures of those polymers.
  • Preferred carriers are water, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose and hydroxypropylcellulose, neutral Carbopol, or mixtures thereof.
  • the concentration of the carrier is, for example, from 0.1 to 100000 times the concentration of the active ingredient combinations thereof and the like.
  • preferred carriers include water, pH buffered saline solution, mixtures thereof and the like.
  • the preferred carrier is an aqueous saline solution containing salts including, without limitation, sodium chloride, sodium borate, sodium phosphate, sodium hydrogenphosphate, sodium dihydrogenphosphate, or the corresponding potassium salts of the same. These ingredients are generally combined to form buffered solutions that include an acid and its conjugate base, so that addition of acids and bases cause only a relatively small change in pH.
  • the buffered solutions may additionally include 2-(N- morpholino)ethanesulfonic acid (MES), sodium hydroxide, 2,2- bis(hydroxymethyl)-2,2',2"-nithlotriethanol, n-tris(hydroxymethyl)methyl-2- aminoethanesulfonic acid, citric acid, sodium citrate, sodium carbonate, sodium bicarbonate, acetic acid, sodium acetate, ethylenediamine tetraacetic acid and the like and combinations thereof.
  • the carrier is a borate buffered or phosphate buffered saline solution.
  • the invention includes an ophthalmic composition
  • an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient and an effective amount of a stabilizing agent.
  • oxidatively unstable pharmaceutical ingredient, effective amount, and stabilizing agents all have their aforementioned meanings and preferred ranges.
  • the invention includes a method of stabilizing an ophthalmic composition comprising an oxidatively unstable excipient wherein said method comprises adding an effective amount of a stabilizing agent to the ophthalmic composition.
  • oxidatively unstable excipient refers to a component of ophthalmic compositions that degrades in the presence of oxygen and certain transition metals. Examples of unstable excipients include but are not limited to astringents, demulcents, emollients, hypertonicity agents, oleaginous, agents, tonicity agents mucomimetic agents, and the like.
  • unstable excipients include but are not limited to cellulose derivatives, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hyaluronic acid, methylcellulose, Dextran, gelatin, polyols, glycerin, polyethylene glycol, polysorbate, propylene glyxol, polyvinyl alcohol, povidone lanolin, mineral oil, paraffin, petrolatum, white ointment, white petrolatum, white, wax, and yellow wax.
  • stabilizing agent and "effective amount” have their aforementioned meanings and preferred ranges.
  • the invention includes an ophthalmic composition
  • an ophthalmic composition comprising an oxidatively unstable excipient and an effective amount of a stabilizing agent.
  • oxidatively unstable excipient stabilized by a stabilizing agent
  • stabilizing agent stabilizing agent
  • effective amount have their aforementioned meanings and preferred ranges.
  • the invention includes a method of stabilizing an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient wherein said method comprises
  • step (b) polymerizing an effective amount of the product of step (a) with at least one type of polymehzable monomer
  • step (c) contacting the ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient with the polymer of step (b).
  • oxidatively unstable pharmaceutical ingredient, effective amount, and stabilizing agents all have their aforementioned meanings and preferred ranges.
  • functionalizing means chemically bonding a polymerizable group to said stabilizing agent.
  • a polymerizable group includes but are not limited to methacrylate, acrylate, acrylamide, and styrene.
  • polymerizable monomer includes compounds containing olefinic moieties capable of adding to radical species, such as propylene, ethylene and the like.
  • the polymerization product of step (b) may be soluble or insoluble in the ophthalmic composition.
  • the polymerization product of step (b) is not soluble in the ophthalmic composition and as such the polymerization product of step (b) may be in any form such as rods, discs, containers, films and the like.
  • the invention includes a method of stabilizing an ophthalmic composition comprising an oxidatively unstable excipient wherein said method comprises
  • step (b) polymerizing an effective amount of the product of step (a) with at least one type of polymehzable monomer
  • step (c) contacting the ophthalmic composition comprising an oxidatively unstable exicipient with the polymer of step (b).
  • oxidatively unstable excipient effective amount, stabilizing agents, polymerizable group, and polymehzable monomers all have their aforementioned meanings and preferred ranges.
  • the invention includes a container for an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient wherein said container comprises the polymerization product of an effective amount of a stabilizing agent functionalized with a polymerizable group and at least one type of polymerizable momoner.
  • oxidatively unstable pharmaceutical ingredient, effective amount, stabilizing agents, polymerizable group, and polymerizable monomers all have their aforementioned meanings and preferred ranges.
  • the invention includes a container for an ophthalmic composition comprising an oxidatively unstable excipient wherein said container comprises the polymerization product of an effective amount of a stabilizing agent functionalized with a polymerizable group and at least one type of polymerizable momoner.
  • oxidatively unstable excipient, effective amount, stabilizing agents, polymerizable group, and polymerizable monomers all have their aforementioned meanings and preferred ranges.
  • ketotifen is known as a oxidatively unstable pharmaceutical ingredient.
  • Compositions containing ketotifen fumarate are known. These compositions contain EDTA and the pH of those compositions is about 5.5. These EDTA solutions stabilize the ketotifen fumarate against oxidative degradation, the pH of these solutions is below the threshold for ocular awareness and it is likely that some patient who use this solution will be uncomfortable due to low pH value of the solution. See Tang, I., Wong, D. M., Yee, D.J. and Harris, M. G. 1996 The pH of multi-purpose soft contact lens solutions. Optom. Vis. Sci. 73:746-749. Adler, F. H.
  • the stabilizing agents of the invention will reduce the degradation of ketotifen fumarate at higher pH values that those of ketotifen fumarate solutions containing EDTA.
  • the pH of ophthalmic compositions of the invention is preferably between about pH 6.6 and about pH 7.2, more preferably between about pH 6.8 and about pH 7.0.
  • PAA Polyacrylic Acid sodium salt having an average molecular weight of 200,000 EDTA
  • Ketotifen Fumarate Solutions with PAA EDTA PAA (2000 ⁇ g/mL) was added to Solution A, and 50 ⁇ g/mL of ketotifen fumarate (approximately 36 ⁇ g/mL of ketotifen) was dissolved in the system.
  • EDTA 100 ⁇ g/mL was added to another batch of Solution A, and 50 ⁇ g/mL of ketotifen fumarate was dissolved in the system.
  • Negative One and negative twelve (-1.0 and 12.0) diopter etafilcon A contact lenses were added to vials containing 3mL of each of the above solutions.
  • Ketotifen fumarate 50 ⁇ g/mL, approximately 36 ⁇ g/mL of ketotifen was dissolved in Solution A containing approximately 500 ⁇ g/mL of either DTPA (approximately 1272 ⁇ moles/L of DTPA) or the sodium salt of EDTA (Na 2 CioHi 4 O 8 N 2 *2 H 2 O, 1344 ⁇ moles/L of EDTA).
  • DTPA approximately 1272 ⁇ moles/L of DTPA
  • EDTA sodium salt of EDTA
  • Approximately 50 ⁇ g/mL of the salts listed in Table 1 were dissolved in each of the solutions and about 3mL of each solution was dosed into several vials The vials were sealed with PTFE coated rubber stoppers and were subjected to zero, one, two or three sterilization cycles as indicated in Table 1.

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Abstract

Ophthalmic compositions and methods of preparing such compositions are disclosed.

Description

METHODS FOR STABILIZING OXIDATIVELY UNSTABLE COMPOSITIONS
FIELD OF THE INVENTION
This invention related to compositions of oxidatively unstable ophthalmic ingredients and methods for preparing such compositions RELATED APPLICATION
This application claims priority from a non-provisional filing, U.S. App. Pat. No. U.S. App. Pat. No. 60/783,557 entitled "Methods for Stabilizing Oxidatively Unstable Pharmaceutical Compositions," which was filed on, March 17, 2006. BACKGROUND
Therapeutic agents for topical administration to the eye are generally formulated in either a liquid or gel form and must be kept sterile until administration. Accordingly, ophthalmic therapeutic agents are either packaged asceptically, which is cumbersome and expensive or are heat sterilized. Unfortunately, many therapeutic agents are not oxidatively stable, especially at elevated temperatures.
EDTA, Dequest, and Desferal have been used to improve the stability of certain therapeutic agents during autoclaving. However, there remains a need for other compounds capable of stabilizing unstable therapeutic agents that are susceptible to oxidative degradation. This need is met by the following invention.
BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 Stability Study with Ketotifen and PAA or EDTA Fig. 2. Stability Study with Ketotifen and PAA or EDTA Fig. 3 Stability Study with Ketotifen and PAA or DTPA
DETAILED DESCRIPTION OF THE INVENTION This invention includes a method of stabilizing an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient wherein said method comprises adding an effective amount of a stabilizing agent to the ophthalmic composition.
As used herein "oxidatively unstable pharmaceutical ingredient" refers to pharmaceutical or nutraceutical compounds used to treat conditions of the eye, and such compound degrade in the presence of oxygen and certain transition metals. Examples of pharmaceutical compounds include antihistamines, antibiotics, antibacterial agents, antiviral agents, antifungal agents, analgesics, anesthetics, antiallergeneic agents, mast cell stabilizers, steroidal and non- steroidal anti-inflammatory agents, angiogenesis inhibitors; antimetabolites, fibrinolytics, neuroprotective drugs, angiostatic steroids, mydriatics, cyclopegic mydriatics; miotics; vasoconstrictors; vasodilators, anticlotting agents; anticancer agents, antisense agents, immunomodulatory agents, carbonic anhydrase inhibitors, integhn antabonistsl; cyclooxygenase inhibitors, VEGF antagonists; immunosuppressant agents and the like. Particularly, examples of pharmaceutical agents include but are not limited to achvastine, antazoline, astemizole, azatadine, azelastine, buclizine, bupivacaine, cetirizine, clemastine, cyclizine, cyproheptadine, ebastine, emedastine, ephedrine, eucatropine, fexofenadine, homatropine, hydroxyzine, ketotifen, levocabastine, levoceterizine, lomefloxacin, meclizine, mepivacaine, mequitazine, methdilazine, methapyrilene, mianserin, naphazoline norastemizole, norebastine, ofloxacin, oxymetazoline, pheniramine, phenylephrine, physostigmine, picumast, promethazine, scopolamine, terfenadine, tetrahydozoline, thiethylperazine, timolol, trimeprazine, triprolidine, pharmaceutically acceptable salts and mixtures thereof. Preferred pharmaceutical compounds include achvatine, antazoline, astemizole, azatadine, azelastine, clemastine, cyproheptadine, ebastine, emedastine, eucatropine, fexofenadine, homatropine, hydroxyzine, ketotife, levocabastine, levoceterizine, meclizine, mequitazine, methdialazine, methapyrilene, norastemizole, norebastine, oxymetazoline, physootigmine, picumast, promethazine, scopolamine, terfenadine, tetrahyerozoline, fimilol, trimeprazine, triprolidine, and pharmaceutically acceptable salts thereof. Particularly preferred pharmaceutical compounds include phenarimine, ketotifen, ketotifen fumarate nor ketotifen, olapatadine and mixtures thereof. More particularly preferred pharmaceutical compounds include ketotifen, its pharmaceutically acceptable salts, and mixtures thereof.
Examples of nutraceutical compounds include vitamins and supplements such as vitamins A, D, E, lutein, zeaxanthin, lipoic acid, flavonoids, ophthalmicially compatible fatty acids, such as omega 3 and omega 6 fatty acids, combinations thereof, combinations with pharmaceutical compounds and the like. Preferred pharmaceutical or nutraceutical compounds are those that degrade when solutions of these compounds and oxidative catalysts (such as metals and metallic salts) are mixed together at ambient or elevated temperatures, as compared to solutions of these compounds without oxidative catalysts at ambient or elevated temperatures. Particularly preferred pharmaceutical or nutraceutical compounds are those that degrade greater than about 10% when heated to about 12O0C for about 20 minutes with oxidative catalysts. The concentration of oxidatively unstable pharmaceutical ingredients in the ophthalmic compositions of the invention range from about 2 μg/mL to about 0.5 g/mL, particularly preferred, about 0.1 μg/mL to about 10,000 μg/mL.
The term "ophthalmic composition" refers to liquids, aerosols, or gels that may be topically administered to the eye. The term "stabilizing agent" refers to chelant compositions that inhibit metal catalyzed oxidative degradation of the oxidatively unstable pharmaceutical ingredient. Examples of stabilizing agents include but are not limited to silica, chitin derivative such as chitosan, polyamides such as poly(aspartic acid-co-ω-amino acid (See CAN:129:54671 , Shibata, Minako et al. Graduate School Environmental Earth Science,
Hokkaido University, Sapporo, Japan Macromolecular Symposia (1998), 130, 229-244) and polymeric amides such as poly[iminocarbonyl(2,5-dihydroxy- 1 ,4-phenylene)carbonylimino-1 ,4-phenylenemethylene-1 ,4-phenylene], CAS # 87912-00-3, polymeric lactams such as polyvinylpyrrolidone, polyamino carboxylic acids such as diethylenethaminepentaacetic acid and triethylenetriaminepentaacetic acid, polymeric amines such as polyallylamine, crown ethers such as 18-crown-6, 21 -crown-7, and 24-crown-8, cellulose and its derivatives, and N, N, N', N', N", N"-hexa(2-pyridyl)-1 ,3,5- ths(aminomethyl)benzene, and certain macrocyclic ligands such as crown ethers, ligand containing knots and catenands (See, David A. Leigh et al Angew. Chem Int. Ed., 2001 , 40, No. 8, pgs. 1538-1542 and Jean-Claude Chambron et al. Pure & Appl. Chem., 1990, Vol. 62, No. 6, pgs. 1027-1034) The preferred stabilizing agents are polyamino carboxylic acids such as diethylenetriaminepentaacetic acid and triethylenetriaminepentaacetic acid. The particulary preferred stabilizing agents are diethylenetriaminepentaacetic acid ("DTPA"), or salts of DTPA such as CaNa3DTPA, ZnNa3DTPA, and Ca2UTPA. The term "effective amount" refers to the amount of stabilizing agent required to inhibit the oxidative degradation of the pharmaceutical ingredient. In most circumstances it is preferred that there is a 1 :1 molar ration of metal present in the ophthalmic composition to chelant, is more preferably about 1 of metal to greater than about 1 of chelant compositions, most preferably about 1 of metal to greater than or equal to about 2 of chelant compositions. With respect to concentration limits, it is preferred that the stabilizing agents have a concentration in the ophthalmic composition from about 2.5 μmoles/liter to about, 5000 μmoles/liter more preferably from about 20 μmoles/liter to about 1000 μmoles/liter, more preferably from about 100 μmoles/liter to about 1000 μmoles/liter, most preferably from about 100 μmoles/liter to about 500 μmoles/liter.
Aside from the oxidatively unstable pharmaceutical ingredient and the stabilizing agent, the ophthalmic composition contains suitable ophthalmic carriers. Suitable carriers include antioxidants (radical scavengers), demulcents, antibacterial agents, solubilizers, surfactants, buffer agents, tonicity adjusting agents, chelating agents, preservatives, wetting agents, thickeners, water, saline solution, mineral oil, petroleum jelly, water soluble solvents, such as Ci5-2o alcohols, Ci5-2o amides, Ci5-2o alcohols substituted with zwittehons, vegetable oils or mineral oils comprising from 0.5 to 5% by weight hydroxyethylcellulose, ethyl oleate, carboxymethylcellulose, polyvinyl- pyrrolidone and other non-toxic water-soluble polymers for ophthalmic uses, such as, for example cellulose derivatives, such as methylcellulose, alkali metal salts of carboxy-methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropyl-cellulose, hydroxypropylcellulose, chitosan and scleroglucan, acrylates or methacrylates, such as salts of poly(acrylic acid) or ethyl acrylate, polyacrylamides, natural products, such as gelatin, alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia, starch derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products, such as poloxamers, e.g. Poloxamer F127, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably cross-linked poly(acrylic acid), such as neutral Carbopol, or mixtures of those polymers. Preferred carriers are water, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose and hydroxypropylcellulose, neutral Carbopol, or mixtures thereof. The concentration of the carrier is, for example, from 0.1 to 100000 times the concentration of the active ingredient combinations thereof and the like. When the ophthalmic composition is an eye drop, preferred carriers include water, pH buffered saline solution, mixtures thereof and the like. The preferred carrier is an aqueous saline solution containing salts including, without limitation, sodium chloride, sodium borate, sodium phosphate, sodium hydrogenphosphate, sodium dihydrogenphosphate, or the corresponding potassium salts of the same. These ingredients are generally combined to form buffered solutions that include an acid and its conjugate base, so that addition of acids and bases cause only a relatively small change in pH. The buffered solutions may additionally include 2-(N- morpholino)ethanesulfonic acid (MES), sodium hydroxide, 2,2- bis(hydroxymethyl)-2,2',2"-nithlotriethanol, n-tris(hydroxymethyl)methyl-2- aminoethanesulfonic acid, citric acid, sodium citrate, sodium carbonate, sodium bicarbonate, acetic acid, sodium acetate, ethylenediamine tetraacetic acid and the like and combinations thereof. Most preferably, the carrier is a borate buffered or phosphate buffered saline solution.
Further the invention includes an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient and an effective amount of a stabilizing agent. The terms oxidatively unstable pharmaceutical ingredient, effective amount, and stabilizing agents all have their aforementioned meanings and preferred ranges.
Still further the invention includes a method of stabilizing an ophthalmic composition comprising an oxidatively unstable excipient wherein said method comprises adding an effective amount of a stabilizing agent to the ophthalmic composition. As used herein "oxidatively unstable excipient" refers to a component of ophthalmic compositions that degrades in the presence of oxygen and certain transition metals. Examples of unstable excipients include but are not limited to astringents, demulcents, emollients, hypertonicity agents, oleaginous, agents, tonicity agents mucomimetic agents, and the like. Particularly examples of unstable excipients include but are not limited to cellulose derivatives, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hyaluronic acid, methylcellulose, Dextran, gelatin, polyols, glycerin, polyethylene glycol, polysorbate, propylene glyxol, polyvinyl alcohol, povidone lanolin, mineral oil, paraffin, petrolatum, white ointment, white petrolatum, white, wax, and yellow wax. The terms "stabilizing agent," and "effective amount" have their aforementioned meanings and preferred ranges.
Yet still further the invention includes an ophthalmic composition comprising an oxidatively unstable excipient and an effective amount of a stabilizing agent. The terms "oxidatively unstable excipient," "stabilizing agent," and "effective amount" have their aforementioned meanings and preferred ranges.
Even further still the invention includes a method of stabilizing an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient wherein said method comprises
(a) functionalizing said stabilizing agent with a polymehzable group,
(b) polymerizing an effective amount of the product of step (a) with at least one type of polymehzable monomer, and
(c) contacting the ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient with the polymer of step (b).
The terms oxidatively unstable pharmaceutical ingredient, effective amount, and stabilizing agents all have their aforementioned meanings and preferred ranges. The term functionalizing means chemically bonding a polymerizable group to said stabilizing agent. Examples of a polymerizable group includes but are not limited to methacrylate, acrylate, acrylamide, and styrene. The term polymerizable monomer includes compounds containing olefinic moieties capable of adding to radical species, such as propylene, ethylene and the like. The polymerization product of step (b) may be soluble or insoluble in the ophthalmic composition. It is preferred that the polymerization product of step (b) is not soluble in the ophthalmic composition and as such the polymerization product of step (b) may be in any form such as rods, discs, containers, films and the like. Even further still the invention includes a method of stabilizing an ophthalmic composition comprising an oxidatively unstable excipient wherein said method comprises
(a) functionalizing said stabilizing agent with a polymehzable group,
(b) polymerizing an effective amount of the product of step (a) with at least one type of polymehzable monomer, and
(c) contacting the ophthalmic composition comprising an oxidatively unstable exicipient with the polymer of step (b).
The terms oxidatively unstable excipient, effective amount, stabilizing agents, polymerizable group, and polymehzable monomers all have their aforementioned meanings and preferred ranges.
Further still the invention includes a container for an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient wherein said container comprises the polymerization product of an effective amount of a stabilizing agent functionalized with a polymerizable group and at least one type of polymerizable momoner. The terms oxidatively unstable pharmaceutical ingredient, effective amount, stabilizing agents, polymerizable group, and polymerizable monomers all have their aforementioned meanings and preferred ranges.
Yet, further still the invention includes a container for an ophthalmic composition comprising an oxidatively unstable excipient wherein said container comprises the polymerization product of an effective amount of a stabilizing agent functionalized with a polymerizable group and at least one type of polymerizable momoner. The terms oxidatively unstable excipient, effective amount, stabilizing agents, polymerizable group, and polymerizable monomers all have their aforementioned meanings and preferred ranges.
The advantages of the compositions and methods of this invention are numerous. First ketotifen is known as a oxidatively unstable pharmaceutical ingredient. Compositions containing ketotifen fumarate are known. These compositions contain EDTA and the pH of those compositions is about 5.5. These EDTA solutions stabilize the ketotifen fumarate against oxidative degradation, the pH of these solutions is below the threshold for ocular awareness and it is likely that some patient who use this solution will be uncomfortable due to low pH value of the solution. See Tang, I., Wong, D. M., Yee, D.J. and Harris, M. G. 1996 The pH of multi-purpose soft contact lens solutions. Optom. Vis. Sci. 73:746-749. Adler, F. H. 1959 Physiology of the Eye. Third edition, p.40. Brawner, L.W. and Jessop, D. G. 1962. A review of contact lens solutions. Contacto 6:49-51. It has been discovered that the stabilizing agents of the invention will reduce the degradation of ketotifen fumarate at higher pH values that those of ketotifen fumarate solutions containing EDTA. The pH of ophthalmic compositions of the invention is preferably between about pH 6.6 and about pH 7.2, more preferably between about pH 6.8 and about pH 7.0. Second it has been shown that the shelf life of ketotifen fumarate solutions containing DTPA are superior to the shelf life of ketotifen fumarate solutions containing either EDTA or PAA. Third, it is known that the application of heat increases the rate of degradation of many pharmaceutical ingredients. It has been shown that the stabilizing agents of this invention are useful in reducing degradation associated with higher temperature, such as sterilization temperatures.
In order to illustrate the invention the following examples are included. These examples do not limit the invention. They are meant only to suggest a method of practicing the invention. Those knowledgeable in contact lenses as well as other specialties may find other methods of practicing the invention. However, those methods are deemed to be within the scope of this invention.
EXAMPLES
The following abbreviations are used below PAA Polyacrylic Acid, sodium salt having an average molecular weight of 200,000 EDTA
Ethylenediamine tetraacetic acid. Solution A
Deionized water containing the following ingredients by weight : NaCI (0.83%), Boric Acid (0.91 %), Sodium tetraborate decahydrate (0.1 %)
Initial Testing to Determine Suitability of Ingredients
It is known that excessive quantities of certain transition metals and their salts will degrade ketotifen fumarate. The amount of metals and salts contained within commercially available ingredients varies, so test batches of Solution A were evaluated as follows. 200 g Solution A was mixed at ambient temperature and ketotifen fumarate (5 mg + 2 mg) was added and mixed until homogenous. Six glass vials were filled with 3ml_ of this solution. The vials were stopped with poly tetrafluoroethylene ("PTFE ") and three of the vials were heated for eighteen minutes at 124 0C. Samples of each treated vial (1.0-1.5 ml_) were analyzed by
HPLC and compared to the untreated controls. If the amount of ketotifen in the treated vials reduced by less than or equal to five percent (<5%) the ingredients were determined to be suitable for further studies and larger batches of Solution A were prepared from these ingredients. Example 1
Preparation of Ketotifen Fumarate Solutions with PAA, EDTA PAA (2000 μg/mL) was added to Solution A, and 50 μg/mL of ketotifen fumarate (approximately 36 μg/mL of ketotifen) was dissolved in the system. EDTA (100 μg/mL) was added to another batch of Solution A, and 50 μg/mL of ketotifen fumarate was dissolved in the system. Negative One and negative twelve (-1.0 and 12.0) diopter etafilcon A contact lenses were added to vials containing 3mL of each of the above solutions. The vials were sealed with PTFE coated rubber stoppers, sterilized at 124 0C for 18 minutes, and stored at ambient temperature for one year. Samples were harvested throughout the year and analyzed for the presence of ketotifen by HPLC. The results are presented in Figures 1 and 2. These results show that there is substantial degradation of the ketotifen over time with PAA and with EDTA. Example 2
Preparation of Ketotifen Fumarate Solutions with PAA, DTPA To separate batches of Solution A, Ca2DTPA (100 μg/mL and 300 μg/mL, 213 and 640 μmoles/L respectively) and 2000 μg/mL (0.2%, approximately 18.51 mmole/L methacrylate content) of PAA were added, and approximately 25 μg/mL of ketotifen fumarate (approximately 18 μg/mL of ketotifen) was dissolved in each of the systems. Three mL samples of each solution were added to individual vials containing contact lenses. Each set of vials was closed with PTFE stoppers, sterilized at 124 0C for 18 minutes, and stored at 8O0C for a period of two weeks. Samples were harvested at various intervals and analyzed for the presence of ketotifen by HPLC. The results are presented in Figure 3. These results show that there is substantial degradation of the ketotifen over time with PAA but not with the calcium salt of DTPA
Example 3
Ketotifen Fumarate Solutions with oxidation catalysts
Ketotifen fumarate (50μg/mL, approximately 36μg/mL of ketotifen) was dissolved in Solution A containing approximately 500 μg/mL of either DTPA (approximately 1272 μmoles/L of DTPA) or the sodium salt of EDTA (Na2CioHi4O8N2*2 H2O, 1344μmoles/L of EDTA). Approximately 50 μg/mL of the salts listed in Table 1 were dissolved in each of the solutions and about 3mL of each solution was dosed into several vials The vials were sealed with PTFE coated rubber stoppers and were subjected to zero, one, two or three sterilization cycles as indicated in Table 1. One sterilization cycle is eighteen minutes of heating at 124 0C. Samples were analyzed by HPLC for the concentration of ketotifen at the intervals indicated in Table 2. This data shows that in the presence of oxidative catalysts, DTPA reduces the amount of oxidative degradation as compared to EDTA. Table 1
Table 2

Claims

What is claimed is
1. A method of stabilizing an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient wherein said method comprises adding an effective amount of a stabilizing agent to the ophthalmic composition.
2. The method of claim 1 wherein the stabilizing agent is selected from the group consisting of silica, chitin derivative such as chitosan, cellulose its derivatives, and N,N,N',N\N", N"-hexa(2-pyridyl)-1 ,3,5- ths(aminomethyl)benzene, diethylenethaminepentaacetic acid, and salts of diethylenethaminepentaacetic.
3. The method of claim 1 wherein the stabilizing agent is selected from the group conisiting of diethylenethaminepentaacetic acid, and salts of diethylenethaminepentaacetic acid.
4. The method of claim 1 wherein the effective amount of the stabilizing agent is about 2.5 μmoles/liter to about 5000 μmoles/liter.
5. The method of claim 1 wherein the effective amount of the stabilizing agent is about 20 μmoles/liter to about 1000 μmoles/liter.
6. The method of claim 1 wherein the effective amount of the stabilizing agent is about 100 μmoles/liter to about 600 μmoles/liter.
7. The method of claim 1 wherein the stabilizing agent is diethylenethaminepentaacetic acid.
8. The method of claim 1 wherein the stabilizing agent is diethylenethaminepentaacetic acid or salts there of and the effective amount of said stabilizing agent is about 100 μmoles/liter to about 1000 μmoles/liter
9. The method of claim 1 wherein the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of acrivastine, antazoline, astemizole, azatadine, azelastine, buclizine, bupivacaine, cetirizine, clemastine, cyclizine, cyproheptadine, ebastine, emedastine, eucatropine, fexofenadine, homatropine, hydroxyzine, ketotifen, levocabastine, levoceterizine, lomefloxacin, meclizine, mepivacaine, mequitazine, methdilazine, methapyrilene, mianserin, norastemizole, norebastine, ofloxacin, oxymetazoline, pheniramine, physostigmine, picumast, promethazine, scopolamine, terfenadine, tetrahydozoline, thiethylperazine, timolol, trimeprazine, triprolidine, pharmaceutically acceptable salts and mixtures thereof.
10. The method of claim 1 wherein the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of acrivatine, antazoline, astemizole, azatadine, azelastine, clemastine, cyproheptadine, ebastine, emedastine, eucatropine, fexofenadine, homatropine, hydroxyzine, ketotifen, levocabastine, levoceterizine, meclizine, mequitazine, methdialazine, methapyrilene, norastemizole, norebastine, oxymetazoline, physootigmine, picumast, promethazine, scopolamine, terfenadine, tetrahyerozoline, fimilol, trimeprazine, triprolidine, and pharmaceutically acceptable salts thereof.
11. The method of claim 1 wherein the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of phenahmine, ketotifen, ketotifen fumarate, nor ketotifen fumarate olopatadine and mixtures thereof.
12. The method of claim 1 wherein the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of ketotifen, its pharmaceutically acceptable salts, and mixtures thereof.
13. The method of claim 1 wherein the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of vitamins A, D, E, lutein, zeaxanthin, lipoic acid, flavonoids, ophthalmicially compatible fatty acids, such as omega 3 and omega 6 fatty acids and combinations thereof.
14. The method of claim 1 wherein the stabilizing agent is diethylenethaminepentaacetic acid or salts there of, the effective amount of said stabilizing agent is about 100 μmoles/liter to about 1000 μmoles/liter, and the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of ketotifen, its pharmaceutically acceptable salts, and mixtures thereof.
15. The method of claim 1 wherein the stabilizing agent is the calcium salt diethylenethaminepentaacetic acid, the effective amount of said stabilizing agent is about 100 μmoles/liter to about 1000 μmoles/liter, and the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of ketotifen, pharmaceutically acceptable salts of ketotifen and mixtures thereof.
16. The method of claim 1 wherein the ophthalmic composition has a pH of about 6.6 to about 7.2.
17. The method of claim 1 wherein the ophthalmic composition has a pH of about 6.8 to about 7.2.
18. An ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient and an effective amount of a stabilizing agent.
19. The ophthalmic composition of claim 18 wherein the stabilizing agent is selected from the group consisting of silica, chitin derivative such as chitosan, cellulose its derivatives, and N, N, N', N', N", N"-hexa(2-pyridyl)-1 ,3,5- ths(aminomethyl)benzene, diethylenethaminepentaacetic acid, and salts of diethylenethaminepentaacetic acid, and acid.
20. The ophthalmic composition of claim 18 wherein the stabilizing agent is selected from the group conisiting of diethylenetriaminepentaacetic acid, and salts of diethylenetriaminepentaacetic acid.
21. The ophthalmic composition of claim 18 wherein the effective amount of the stabilizing agent is about 2.5 μmoles/liter to about 5000 μmoles/liter.
22. The ophthalmic composition of claim 18 wherein the effective amount of the stabilizing agent is about 100 μmoles/liter to about 1000 μmoles/liter.
23. The ophthalmic composition of claim 18 wherein the effective amount of the stabilizing agent is about 100 μmoles/liter to about 600 μmoles/liter.
24. The ophthalmic composition of claim 18 wherein the stabilizing agent is diethylenethaminepentaacetic acid.
25. The ophthalmic composition of claim 18 wherein the stabilizing agent is diethylenethaminepentaacetic acid or salts there of and the effective amount of said stabilizing agent is about 100 μmoles/liter to about 1000 μmoles/liter
26. The ophthalmic composition of claim 18 wherein the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of achvastine, antazoline, astemizole, azatadine, azelastine, buclizine, bupivacaine, cetirizine, clemastine, cyclizine, cyproheptadine, ebastine, emedastine, eucatropine, fexofenadine, homatropine, hydroxyzine, ketotifen, levocabastine, levoceterizine, lomefloxacin, meclizine, mepivacaine, mequitazine, methdilazine, methapyrilene, mianserin, norastemizole, norebastine, ofloxacin, oxymetazoline, pheniramine, physostigmine, picumast, promethazine, scopolamine, terfenadine, tetrahydozoline, thiethylperazine, timolol, trimeprazine, thprolidine, pharmaceutically acceptable salts and mixtures thereof.
27. The ophthalmic composition of claim 18 wherein the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of achvatine, antazoline, astemizole, azatadine, azelastine, clemastine, cyproheptadine, ebastine, emedastine, eucatropine, fexofenadine, homatropine, hydroxyzine, ketotifen, levocabastine, levoceterizine, meclizine, mequitazine, methdialazine, methapyrilene, norastemizole, norebastine, oxymetazoline, physootigmine, picumast, promethazine, scopolamine, terfenadine, tetrahyerozoline, fimilol, trimeprazine, thprolidine, and pharmaceutically acceptable salts thereof.
28. The ophthalmic composition of claim 18 wherein the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of phenarimine, ketotifen, ketotifen fumarate nor ketotifen fumarate, olopatadine and mixtures thereof.
29. The ophthalmic composition of claim 18 wherein the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of ketotifen, its pharmaceutically acceptable salts, and mixtures thereof.
30. The ophthalmic composition of claim 18 wherein the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of vitamins A,
D, E, lutein, zeaxanthin, lipoic acid, flavonoids, ophthalmicially compatible fatty acids, such as omega 3 and omega 6 fatty acids and combinations thereof.
31. The ophthalmic composition of claim 18 wherein the stabilizing agent is diethylenethaminepentaacetic acid or salts there of, the effective amount of said stabilizing agent is about 200 μmoles/liter to about 1000 μmoles/liter, and the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of ketotifen, its pharmaceutically acceptable salts, and mixtures thereof.
32. The ophthalmic composition of claim 18 wherein the stabilizing agent is the calcium salt diethylenetriaminepentaacetic acid, the effective amount of said stabilizing agent is about 100 μmoles/liter to about 1000 μmoles/liter, and the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of ketotifen, pharmaceutically acceptable salts of ketotifen and mixtures thereof.
33. The ophthalmic composition of claim 18 wherein the pH is about 6.6 to about 7.2.
34. The ophthalmic composition wherein the pH is about 6.8 to about 7.2.
35. A method of stabilizing an ophthalmic composition comprising an oxidatively unstable excipient wherein said method comprises adding an effective amount of a stabilizing agent to the ophthalmic composition.
36. The method of claim 35 wherein the oxidatively unstable excipient is selected from the group consisting of cellulose derivatives, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hyaluronic acid, methylcellulose, Dextran, gelatin, polyols, glycerin, polyethylene glycol, polysorbate, propylene glyxol, polyvinyl alcohol, povidone lanolin, mineral oil, paraffin, petrolatum, white ointment, white petrolatum, white, wax, and yellow wax.
37. The method of claim 35 wherein the stabilizing agent is selected from the group consisting of silica, chitin derivative such as chitosan, cellulose its derivatives, and N, N, N', N', N", N"-hexa(2-pyridyl)-1 ,3,5- ths(aminomethyl)benzene, diethylenethaminepentaacetic acid, and salts of diethylenethaminepentaacetic acid.
38. The method of claim 35 wherein the stabilizing agent is selected from the group conisiting of diethylenetriaminepentaacetic acid, and salts of diethylenethaminepentaacetic acid.
39. The method of claim 35 wherein the effective amount of the stabilizing agent is about 20 μmoles/liter to about 1000 μmoles/liter.
40. The method of claim 35 wherein the effective amount of the stabilizing agent is about 100 μmoles/liter to about 600 μmoles/liter.
41. The method of claim 35 wherein the stabilizing agent is diethylenethaminepentaacetic acid.
42. The method of claim 35 wherein the stabilizing agent is diethylenethaminepentaacetic acid or salts there of and the effective amount of said stabilizing agent is about 100 μmoles/liter to about 1000 μmoles/liter
43. The method of claim 35 wherein the stabilizing agent is the calcium salt diethylenethaminepentaacetic acid, the effective amount of said stabilizing agent is about 100 μmoles/liter to about 1000 μmoles/liter, and the oxidatively unstable excipient is selected from the group consisting of carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hyaluronic acid, methylcellulose, Dextran, gelatin, polyols, glycerin, polyethylene glycol, polysorbate, propylene glyxol, polyvinyl alcohol, and mixtures thereof.
44. The method of claim 35 wherein the ophthalmic composition has a pH of about 6.6 to about 7.2.
45. The method of claim 35 wherein the ophthalmic composition has a pH of about 6.8 to about 7.2.
46. An ophthalmic composition comprising an oxidatively unstable excipient and an effective amount of a stabilizing agent.
47. The ophthalmic composition of claim 46 wherein the stabilizing agent is selected from the group consisting of silica, chitin derivative such as chitosan, cellulose its derivatives, and N, N, N', N', N", N"-hexa(2-pyridyl)-1 ,3,5- ths(aminomethyl)benzene, diethylenethaminepentaacetic acid, and salts of diethylenethaminepentaacetic acid, and acid.
48. The ophthalmic composition of claim 46 wherein the stabilizing agent is selected from the group conisiting of diethylenetriaminepentaacetic acid, and salts of diethylenetriaminepentaacetic acid.
49. The ophthalmic composition of claim 46 wherein the effective amount of the stabilizing agent is about 20 μmoles/liter to about 1000 μmoles/liter.
50. The ophthalmic composition of claim 46 wherein the effective amount of the stabilizing agent is about 100 μmoles/liter to about 600 μmoles/liter.
51. The ophthalmic composition of claim 46 wherein the stabilizing agent is diethylenetriaminepentaacetic acid.
52. The ophthalmic composition of claim 46 wherein the stabilizing agent is diethylenetriaminepentaacetic acid or salts there of and the effective amount of said stabilizing agent is about 100 μmoles/liter to about 1000 μmoles/liter
53. The ophthalmic composition of claim 46 wherein the stabilizing agent is the calcium salt diethylenetriaminepentaacetic acid, the effective amount of said stabilizing agent is about 100 μmoles/liter to about 1000 μmoles/liter, and the oxidatively oxidatively unstable excipient is selected from the group consisting of carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hyaluronic acid, methylcellulose, Dextran, gelatin, polyols, glycerin, polyethylene glycol, polysorbate, propylene glyxol, polyvinyl alcohol, and mixtures thereof.
54. The ophthalmic composition of claim 46 wherein the pH is about 6.6 to about 7.2.
55. The ophthalmic composition of claim 46 wherein the pH is about 6.8 to about 7.2.
56. A method of stabilizing an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient wherein said method comprises
(a) functionalizing said stabilizing agent with a polymehzable group,
(b) polymerizing an effective amount of the product of step (a) with at least one type of polymehzable monomer, and
(c) contacting the ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient with the polymer of step (b).
57. The method of claim 56 wherein the stabilizing agent is selected from the group consisting of silica, chitin derivative such as chitosan, cellulose its derivatives, and N,N,N',N\N", N"-hexa(2-pyridyl)-1 ,3,5- ths(aminomethyl)benzene, diethylenethaminepentaacetic acid, and salts of diethylenethaminepentaacetic acid, and acid.
58. The method of claim 56 wherein the stabilizing agent is selected from the group consisting of diethylenetriaminepentaacetic acid, and salts of diethylenethaminepentaacetic acid.
59. A method of stabilizing an ophthalmic composition comprising an oxidatively unstable excipient wherein said method comprises
(a) functionalizing said stabilizing agent with a polymehzable group,
(b) polymerizing an effective amount of the product of step (a) with at least one type of polymehzable monomer, and
(c) contacting the ophthalmic composition comprising an oxidatively unstable exicipient with the polymer of step (b).
60. The method of claim 59 wherein the stabilizing agent is selected from the group consisting of silica, chitin derivative such as chitosan, cellulose its derivatives, and N,N,N',N\N", N"-hexa(2-pyridyl)-1 ,3,5- ths(aminomethyl)benzene, diethylenetriaminepentaacetic acid, and salts of diethylenetriaminepentaacetic acid, and acid.
61. The method of claim 59 wherein the stabilizing agent is selected from the group consisting of diethylenetriaminepentaacetic acid, and salts of diethylenethaminepentaacetic acid.
62. A container for an ophthalmic composition comprising an oxidatively unstable excipient wherein said container comprises the polymerization product of an effective amount of a stabilizing agent functionalized with a polymehzable group and at least one type of polymehzable momoner.
63. The container of claim 62 wherein the stabilizing agent is selected from the group consisting of silica, chitin derivative such as chitosan, cellulose its derivatives, and N,N,N',N\N", N"-hexa(2-pyridyl)-1 ,3,5- ths(aminomethyl)benzene, diethylenetriaminepentaacetic acid, and salts of diethylenetriaminepentaacetic acid, and acid.
64. The container of claim 62 wherein the stabilizing agent is selected from the group consisting of diethylenetriaminepentaacetic acid, and salts of diethylenetriaminepentaacetic acid.
65. A container for an ophthalmic composition comprising an oxidatively unstable excipient wherein said container comprises the polymerization product of an effective amount of a stabilizing agent functionalized with a polymehzable group and at least one type of polymerizable momoner.
66. The container of claim 65 wherein the stabilizing agent is selected from the group consisting of silica, chitin derivative such as chitosan, cellulose its derivatives, and N,N,N',N\N", N"-hexa(2-pyridyl)-1 ,3,5- ths(aminomethyl)benzene, diethylenetriaminepentaacetic acid, and salts of diethylenetriaminepentaacetic acid, and acid.
67. The container of claim 65 wherein the stabilizing agent is selected from the group consisting of diethylenetriaminepentaacetic acid, and salts of diethylenetriaminepentaacetic acid.
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Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0710085B8 (en) * 2006-03-31 2021-05-25 Vistakon Pharmaceutical Llc ophthalmic compositions and their kits
EP2471507B1 (en) 2006-09-29 2017-03-01 Johnson & Johnson Vision Care, Inc. Ophthalmic devices used in the treatment of ocular allergies
US20090239954A1 (en) * 2008-03-19 2009-09-24 Collins Gary L Phosphate buffered ophthalmic solutions displaying improved efficacy
US20100226999A1 (en) * 2009-03-06 2010-09-09 Tracy Quevillon-Coleman Process for forming stabilized ophthalmic solutions
IT1393419B1 (en) 2009-03-19 2012-04-20 Medivis S R L OPHTHALMIC COMPOSITIONS OF OMEGA-3 AND OMEGA-6 POLYSATURATED FATTY ACIDS.
JP5675183B2 (en) * 2009-06-16 2015-02-25 ロート製薬株式会社 Aqueous composition
US20120225918A1 (en) 2011-03-03 2012-09-06 Voom, Llc Compositions and Methods for Non-Surgical Treatment of Ptosis
TWI713618B (en) * 2015-10-29 2020-12-21 日商帝化製藥股份有限公司 External preparation
BR112020018377A2 (en) 2018-03-09 2021-03-09 Portola Pharmaceuticals, Inc METHODS OF USE AND PHARMACEUTICAL COMPOSITIONS OF A SELECTIVE SYK INHIBITOR
US10814001B1 (en) 2019-05-06 2020-10-27 Rvl Pharmaceuticals, Inc. Oxymetazoline compositions
US20230285564A1 (en) * 2020-07-30 2023-09-14 Rohto Pharmaceutical Co., Ltd. Aqueous Composition

Family Cites Families (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4304762A (en) * 1978-09-27 1981-12-08 Lever Brothers Company Stabilization of hydrogen peroxide
DD150694A1 (en) * 1980-04-16 1981-09-16 Gisela Raether METHOD FOR STABILIZING PHARMACEUTICAL PREPARATES WITH OXIDATING SENSITIVITIES
DE3640708C2 (en) * 1986-11-28 1995-05-18 Schering Ag Improved pharmaceuticals containing metals
ATE141803T1 (en) * 1988-08-04 1996-09-15 Ciba Geigy Ag METHOD FOR PRESERVING OPHTHALMIC SOLUTIONS AND COMPOSITIONS THEREOF
US5514732A (en) * 1993-07-22 1996-05-07 Johnson & Johnson Vision Products, Inc. Anti-bacterial, insoluble, metal-chelating polymers
WO1995025518A1 (en) 1994-03-18 1995-09-28 Ciba-Geigy Ag Aqueous solution of levocabastine for ophthalmic use
JPH07324034A (en) 1994-05-30 1995-12-12 Toa Yakuhin Kk Eye drop containing ketotifen fumarate
US5683993A (en) 1995-06-22 1997-11-04 Ciba Vision Corporation Compositions and methods for stabilizing polymers
US6020373A (en) * 1995-10-20 2000-02-01 Eastern Virginia Medical School Chelate derivatives as protectors against tissue injury
RU2140236C1 (en) * 1996-08-20 1999-10-27 Хабаровский филиал МНТК "Микрохирургия глаза" Method of treatment of patients with diabetic retinopathy
AR002194A1 (en) * 1997-03-17 1998-01-07 Sanchez Reynaldo Alemany COMPUTERIZED INSTRUMENT FOR THE ANALYSIS OF MOVEMENT.
US5980882A (en) * 1997-04-16 1999-11-09 Medeva Pharmaceuticals Manufacturing Drug-resin complexes stabilized by chelating agents
JPH11189528A (en) * 1997-12-26 1999-07-13 Lead Chemical Co Ltd Dermal preparation with improved stability
EP0938896A1 (en) * 1998-01-15 1999-09-01 Novartis AG Autoclavable pharmaceutical compositions containing a chelating agent
JPH11279205A (en) * 1998-03-26 1999-10-12 Nippon Tenganyaku Kenkyusho:Kk Method for inhibiting degradation of hyaluronic acid preparations
JP2002510627A (en) 1998-04-02 2002-04-09 ノバルティス アクチエンゲゼルシャフト Method for stabilizing pharmaceutical compositions by special use of antioxidants
DE69900207T2 (en) 1998-07-14 2001-11-22 Alcon Laboratories, Inc. USE OF 11- (3-DIMETHYLAMINOPROPYLIDES) -6.11-DIHYDRODIBENCE [B, E] OXEPIN-2-ACETIC ACID AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS FOR THE PRODUCTION OF A MEDICINE FOR THE TREATMENT, NEDULATION, NEDULATION, NEDULATION, NEDULATION, NEDERATION, NEDULATION, NEDICULATION, NEDERATION, NON-DENTALIZATION
US6395756B2 (en) 1999-12-23 2002-05-28 Novartis Ag Use of ophthalmic agent
RU2196594C2 (en) * 2000-09-25 2003-01-20 Общество с ограниченной ответственностью "Камелия НПП" Agent eliciting recovery, tonic and regenerative effect
DE60104872T2 (en) * 2000-09-28 2005-09-01 Novartis Ag Stabilized ophthalmic hydrogen peroxide solution
TW586946B (en) * 2000-12-22 2004-05-11 Novartis Ag Process to improve stability
RU2191012C1 (en) * 2001-06-20 2002-10-20 Научно-исследовательский испытательный центр (медико-биологической защиты) Государственного научно-исследовательского испытательного института военной медицины МО РФ Ophthalmic drops for treatment of endothelial-epithelial dystrophy
RU2201213C1 (en) * 2001-07-04 2003-03-27 Общество с ограниченной ответственностью "Научно-экспериментальное производство Микрохирургия глаза" Ophthalmic drop "karnosin"
AU2002360939A1 (en) * 2001-11-21 2003-06-10 Novartis Ag Composition for stabilizing hyaluronic acid
AR038299A1 (en) * 2002-01-18 2005-01-12 Novartis Ag METHODS TO PRESERVE OPHTHALMIC SOLUTIONS AND CONSUMED OPHTHALMIC SOLUTIONS
NZ540885A (en) * 2002-12-20 2009-02-28 Chakshu Res Inc Ophthalmic formulation for the prevention and treatment of ocular conditions
US20050244509A1 (en) * 2004-03-17 2005-11-03 Fu-Pao Tsao Ophthalmic solutions
US20070077303A1 (en) 2005-09-30 2007-04-05 Azaam Alli Methods for providing oxidatively stable ophthalmic compositions
EP2471507B1 (en) * 2006-09-29 2017-03-01 Johnson & Johnson Vision Care, Inc. Ophthalmic devices used in the treatment of ocular allergies

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007109523A2 *

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US8466174B2 (en) 2013-06-18
WO2007109523A2 (en) 2007-09-27
BRPI0709549A2 (en) 2011-07-19
KR20150017002A (en) 2015-02-13
US20180050026A1 (en) 2018-02-22
WO2007109523A3 (en) 2008-04-10
JP2009530314A (en) 2009-08-27
CN101420934A (en) 2009-04-29
AU2007227091B2 (en) 2013-02-07
RU2462234C2 (en) 2012-09-27
AR059927A1 (en) 2008-05-07
TW200808355A (en) 2008-02-16
JP5275214B2 (en) 2013-08-28
CA2646424C (en) 2015-12-29
CA2646424A1 (en) 2007-09-27
CA2908828C (en) 2018-01-16
TWI454286B (en) 2014-10-01
RU2012125612A (en) 2013-12-27
US20170007592A1 (en) 2017-01-12
KR101454674B1 (en) 2014-10-27
RU2008141172A (en) 2010-04-27
KR20140083056A (en) 2014-07-03
KR20080111065A (en) 2008-12-22
EP2010143B1 (en) 2015-08-12
CA2908828A1 (en) 2007-09-27
AU2007227091A1 (en) 2007-09-27
US20140011843A1 (en) 2014-01-09
HK1127998A1 (en) 2009-10-16
US20070265234A1 (en) 2007-11-15
US9474746B2 (en) 2016-10-25
HK1132176A1 (en) 2010-02-19
CN101420934B (en) 2014-03-19

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